Project Summary As of 2015, more than 7 million Americans were living with an implanted artificial joint. While these devices improve the lives of many, over 250,000 of these individuals will eventually require a costly and painful revision surgery due to aseptic loosening of the device from the bone. This type of device failure typically stems from the immune response to microparticles that are generated due to wear between the articular surfaces. Thus, a comprehensive approach to increasing the functional life span of joint replacement devices must include a strategy for controlling the body's response to these particles. Tumor necrosis factor-? (TNF?) has emerged as a compelling target for controlling the foreign body response to microparticles. However, the half-life of anti- TNF therapeutics acting from within the joint is short, and thus this strategy is limited by the need for frequent (e.g., weekly) drug administration for effective treatment. To enable longer acting anti-TNF drug activity, Valitor has developed a patented platform technology for generating soluble clusters of therapeutic antibodies attached to single-chain biopolymers. In contrast to other methods of protein-polymer conjugation (e.g., PEGylation), our method of conjugation generates substantially larger conjugates with enhanced drug potency. In fact, our anti-TNF? antibody conjugates (mvAntiTNF) are even larger than the tissue meshwork that lines the inside of the joint, and therefore we anticipate mvAntiTNF will be retained within the joint at least 12 times longer than an unmodified antibody after intra-articular injection. During Phase I, we will verify that increasing the molecular size of mvAntiTNF conjugates will provide longer-acting inhibition of the immune responses to microparticles in the joint space and prevent implant loosening over time. Our proposed study will provide proof-of-concept that anti-TNF conjugates can generate sustained treatment effects in the joint. We expect this mvAntiTNF therapy will follow a well-defined route to FDA market approval and commercialization, which we will continue during the next phase of this project.